Abstract Previous studies show that mental stress-induced ischemia is characteristically silent, may account for up to 75% of the total ischemic burden experienced during normal daily life, and is associated with worse long term outcome. However, the coronary and peripheral vascular changes that accompany mental stress in patients with coronary artery disease (CAD) with and without ischemia during mental stress have not been investigated, and are likely to be crucial in providing understanding of the underiying mechanisms that lead to increased risk in these patients. The overall goal of the project is to investigate whether abnormal vascular reactivity of (a) the coronary and/or (b) peripheral vasculature and (c) a pro-inflammatory response contribute to myocardial ischemia during mental stress in subjects with CAD. This will: 1) provide a mechanistic understanding of the underiying coronary and peripheral vascular alterations and systemic inflammatory changes that accompany mental stress in patients with CAD, and how they contribute to myocardial ischemia; 2) identify peripheral vascular and/or inflammatory predictors of mental stress-induced ischemia (MSI) during SPECT; and 3) determine whether subjects who have a more abnormal reaction to mental stress testing, by repeated exposure to daily life psychologic stressors, develop greater vascular dysfunction and more severe systemic inflammation during follow-up. The results of our studies will assist development of 1) specific therapeutic approaches for treatment of MSI that is associated with adverse long term outcome, and 2) new model of mental stress-based stress testing for prognostic evaluation conventionally evaluated by exercise or pharmacologic tests.